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Short-term trivalent arsenic and hexavalent chromium exposures induce gut dysbiosis and transcriptional alteration in adipose tissue of mice

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Abstract

Background

Inorganic arsenic [As(III)] and hexavalent chromium [Cr(VI)] can potentially affect metabolic functions. These heavy metal(s)/metalloids can also affect the gut microbial architecture which affects metabolic health. Here, we assessed the effects of short-term exposure of As(III) and Cr(VI) on key transcription factors in adipose tissues and on selected gut microbial abundances to understand the possible modulatory role of these toxicants on host metabolic health.

Methods and results

qRT-PCR based relative bacterial abundance studies in cecal samples, gene expression analysis for gut wall integrity in ileum and colon and adipogenesis, lipolysis, and thermogenic genes in gonadal white and brown adipose tissue (gWAT and BAT), along with tissue oxidative stress parameters have been performed. As(III) and Cr(VI) exposure reduced beneficial Lactobacilli, Bifidobacteria, Akkermansia, Lachenospiraceae, Fecalibacterium, Eubacterium, and clostridium coccoid group while increasing lipopolysaccharides producing Enterobacteriaceae abundances. It also impaired structural features and expression of key tight junction and mucin production genes in ileum and colon (Cld-2, Cld-4, ZO-1, ZO-2, MUC-2 and − 4). In gWAT it inhibited adipogenesis (PPARγ, FASN, SREBP1a), lipolysis (HSL, ACOX-1), and thermogenesis (UCP-1, PGC1a, PRDM-16, PPARa) related genes expression, whereas in BAT, it enhanced adipogenesis and reduced thermogenesis. These exposures also reduces the endogenous antioxidants levels in these tissues and promote pro-inflammatory cytokines genes expression (TLRs, IL-6, MCP-1). The combinatorial exposure appears to have more deleterious effects.

Conclusion

These effects of As(III) and Cr(VI) may not directly be linked to their known toxicological effects, instead, more intriguing crosstalk with gut microbial ecosystem hold the key.

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Data availability

All the research data and available materials requests can be sent to the corresponding author. Data and materials would be available on reasonable requests.

Abbreviations

ACC:

Acetyl-CoA carboxylase

ACOX-1:

Acyl-CoA Oxidase 1

AKK:

Akkermansia sp.

ANERO:

Anaerostipes sp.

As(III):

Inorganic arsenic

BACT:

Bacteroidetes

BACT sp:

Bacteroides sp.

BAT:

Brown adipose tissue

BCA:

Bicinchoninic acid

BIF:

Bifidobacteria

BPULL:

Butyricicoccus pullicaecorum

BVIB:

Butyrivibrio sp.

CEBPa:

CCAAT/enhancer-binding protein alpha

CITRO:

Citrobacter sp.

Cld:

Claudin

CLEP:

Clostridium sp.

CPCSEA:

Committee for the purpose of control and supervision of experiments on animals

CPROP:

Clostridium propionicum

Cr(VI):

Hexavalent chromium

CRONO:

Cronobacter sp.

DIO2:

Type II iodothyronine deiodinase

ECOL:

Escherichia coli

ENT:

Enterobacter sp.

ENTB:

Enterobacteriaceae

EUBACT:

Eubacterium sp.

F4/80:

EGF-like module-containing mucin-like hormone receptor-like 1

FASN:

Fatty acid synthase

FEC:

Fecalibacterium sp.

FFAR:

Free fatty acid receptors

FIRM:

Firmicutes

gCCOC:

Clostridium coccoides group

GK:

Glucokinase

GLP-1:

Glucagon like peptide-1

GST:

Glutathione-S-Transferase

gWAT:

Gonadal white adipose tissue

HSL:

Hormone-sensitive lipase

IAEC:

Institutional Animal Ethics Committee

ICMR:

Indian Council of Medical Research

IL-6:

Interleukin-6

iNOS:

Inducible nitric oxide synthase

LAB:

Lactobacilli

LACH:

Lachnospiraceae

Lep:

Leptin

LepR:

Leptin receptor

MCP-1:

Macrophage chemoattractant protein-1

MDA:

Malondialdehyde

MUC:

Mucin

MyD88:

Myeloid differentiation primary response 88

NF-kB:

Nuclear factor-kappa beta

PEPCK:

Phosphoenolpyruvate carboxykinase

PGC1α:

Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha

PLIN-1:

Perilipin-1

PPAR (α or γ):

Peroxisome proliferator-activated receptor (alpha or gamma)

PRDM16:

PR domain containing 16

PREVO:

Prevotella sp.

ROS:

Roseburia sp.

SALM:

Salmonella sp.

SOD:

Superoxide dismutase

SREBP1a:

Sterol regulatory element-binding protein 1

TLR:

Toll-like receptor

UCP-1:

Uncoupling protein-1

ZO:

Zona occluding

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Acknowledgements

Authors would like to acknowledge the support of the Director, ICMR-NIOH for the infrastructural and institutional facilities.

Funding

No separate funding was available to declare for this study. Funders have no role in study design, data analysis, and the decision to submit it for publication.

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Author notes

  1. Keya Patel and Shirali Patel have contributed equally to this work.

Authors and Affiliations

  1. Division of Biological Sciences, ICMR-National Institute of Occupational Health, Meghani Nagar, Ahmedabad, Gujarat, 380016, India

    Dhirendra Pratap Singh, Shiv Kumar Yadav, Gajanan Pratap Patil, Vandana Bijalwan, Gyanendra Singh, Rajendra Palkhade & Santasabuj Das

  2. Department of Biological and Lifesciences, School of arts and sciences, Ahmedabad University, Ahmedabad, Gujarat, 380009, India

    Keya Patel & Shirali Patel

  3. Department of Food and Nutritional Biotechnology, National Agri-food Biotechnology Institute, Knowledge City-Sector 81, SAS Nagar, Punjab, 140603, India

    Kanthi Kiran Kondepudi, Ravneet Kaur Boparai & Mahendra Bishnoi

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Contributions

DPS: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigations, Methodology, Project administration, Supervision, Visualizations, Writing-original draft, Review, and editing; SKY: Investigations, Writing-original draft; KP: Investigations, Writing-original draft; SP: Investigations, Writing-original draft; VB: Data curation, Visualization, writing original draft, review, and editing; GPP: Investigations, GS: Resources; RP: Resources, KKK: Conceptualization, Methodology; RKB: Data curation, writing original draft; MB: Methodology, Writing-original draft, Review, and editing; SD: Conceptualization, review and editing.

Corresponding authors

Correspondence to Dhirendra Pratap Singh or Santasabuj Das.

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The authors have no relevant financial or non-financial interests to disclose.

Ethical approval

Suitable ethical clearances (IAEC/NIOH/2020-21/23/# 8) were obtained for the use of tissue samples at the terminal time point from the institutional animal ethics committee of the ICMR-NIOH, Ahmedabad.

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Singh, D.P., Yadav, S.K., Patel, K. et al. Short-term trivalent arsenic and hexavalent chromium exposures induce gut dysbiosis and transcriptional alteration in adipose tissue of mice. Mol Biol Rep 50, 1033–1044 (2023). https://doi.org/10.1007/s11033-022-07992-z

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